The Role of Gut Microbiome Bacteria in the Pathogenesis of Autism Spectrum Disorder

Lindsey Farmer

 Introduction Autism Spectrum Disorder (ASD) includes a range of developmental neuro-behavioral disorders characterized by restricted and repetitive behavior, abnormal social interaction and impaired communication1,2,7. 1 in 68 people in the US have ASD, and the prevalence has increased over 10 fold in the last 40 years, representing some of the greatest burden of childhood disease11. Up to 83% of ASD patients experience co-morbidities, including GI disturbances and particular eating habits5. Research suggests that ASD children have an overgrowth of Clostridium in their microbial flora, leading to an overproduction of bacterial metabolites such as HPHPA, propionic acid (PPA), and butyrate (BA)1,2,6,7,9,10. These metabolites could be neurotoxic and induce autistic behaviors1,2,4,6. How these kids acquire dysbiosis is yet to be elucidated, but the data suggest a potential antibiotic/probiotic or fecal transplant therapy for ASD. Methods A murine model of ASD (mice exposed to valproic acid in utero) was used to determine the relationship between gut microbiota and autism-like behavior. Sequencing technology was used to determine microbiota composition and levels of short chain fatty acids (SCFA) and lactic acid in caecal content1. 8 different rats were administered 250 mg/kg oral PPA and 8 controls were given saline. Markers for oxidative stress, neurotransmission, energy metabolism, apoptosis, and neuroinflammation were measured in brain tissue homogenates4. Results The valproic acid exposed mice had affected levels of Bacteroidetes and Firmicutes, supporting the data from human studies of ASD. The microbial differences were seen more drastically in the male mice, mirroring the human disease’s preponderance for males. Increased levels of butyrate and decreased social behavior scores were denoted2. Similar behavioral abnormalities reflecting ASD characteristics were observed in the PPA exposed rats, along with an increase in oxidative stress markers, decrease in glutathione, impaired energy metabolism, and elevated inflammation/pro-apoptotic markers4Conclusion The data support that autistic behavior can be linked to the gut microbiome and are related to altered microbial colonization and activity in mice models. The effects of overgrowth of bacteria, such as Clostridia, lead to increased levels of short chain fatty acids such as PPA which proved to be neurotoxic and induce autistic behavior. The study points to the microbiome as a main etiological agent in the biochemical features of autistic patients and suggest microbiome manipulation as a future treatment option.

  1.  De Angelis M, Francavilla R, Piccolo M, De Giacomo A, Gobbetti M. Autism spectrum disorders and intestinal microbiota. Gut Microbes. 2015;6(3):207-213.
  2. de Theije CGM, Wopereis H, Ramadan M, et al. Altered gut microbiota and activity in a murine model of autism spectrum disorders. Brain, Behavior, and Immunity. 2014;37:197-206.
  3. Dyck LE, Kazakoff CW, Dourish CT. The role of catecholamines, 5-hydroxytryptamine and m-tyramine in the behavioural effects of m-tyrosine in the rat. European Journal of Pharmacology. 1982;84(3):139-149.
  4. El-Ansary AK, Bacha AB, Kotb M. Etiology of autistic features: the persisting neurotoxic effects of propionic acid. Journal of Neuroinflammation. 2012;9(1):74.
  5. Keşli R, Gökçen C, Buluğ U, Terzi Y. Investigation of the Relation Between Anareobic Bacteria Genus Clostridium and Late-Onset Autism Etiology in Children. Journal of Immunoassay and Immunochemistry. 2014;35(1):101-109.
  6. Fluegge K. Propionic acid metabolism, ASD, and vitamin B12: Is there a role for environmental nitrous oxide? Int J Dev Neurosci.
  7. Li Q, Zhou JM. The microbiota-gut-brain axis and its potential therapeutic role in autism spectrum disorder. Neuroscience. 2016;324:131-139.
  8. Disturbances and Autism Spectrum Disorders. Drug metabolism and disposition: the biological fate of chemicals. 2015;43(10):1557-1571.
  9. Shaw W. Increased urinary excretion of a 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA), an abnormal phenylalanine metabolite of Clostridia spp. in the gastrointestinal tract, in urine samples from patients with autism and schizophrenia. Nutritional Neuroscience. 2010;13(3):135-143.
  10. Strati F, Cavalieri D, Albanese D, et al. New evidences on the altered gut microbiota in autism spectrum disorders. Microbiome. 2017;5(1):24.
  11. Witters P, Debbold E, Crivelly K, et al. Autism in patients with propionic acidemia. Molecular Genetics and Metabolism. 2016;119(4):317-321.
  12. Xiong X, Liu D, Wang Y, Zeng T, Peng Y. Urinary 3-(3-Hydroxyphenyl)-3-hydroxypropionic Acid, 3-Hydroxyphenylacetic Acid, and 3-Hydroxyhippuric Acid Are Elevated in Children with Autism Spectrum Disorders. BioMed Research International. 2016;2016:8.